Dkk1 Controls Cell-Cell Interaction through Regulation of Non-nuclear β-Catenin Pools

• Published in: Developmental cell Vol. 51; no. 6; pp. 775 - 786.e3
• Main Authors: Johansson, Marie, Giger, Florence A., Fielding, Triona, Houart, Corinne
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.12.2019; Cell Press
• Subjects: Animals; beta Catenin - metabolism; cell adhesion; Cell Communication - physiology; cell migration; Cell Movement - physiology; Dickkopf-1; Dkk1; Intercellular Signaling Peptides and Proteins - metabolism; metastasis; neurodegeneration; polarity; Wnt Proteins - metabolism; Wnt signaling morphogenesis; Wnt Signaling Pathway - physiology; Zebrafish; Zebrafish Proteins - metabolism; β-catenin; β-catenin; Dickkopf-1; metastasis; cell adhesion; cell migration; Wnt signaling morphogenesis; neurodegeneration; Dkk1; polarity
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2019.10.026

Dickkopf-1 (Dkk1) is a secreted Wnt antagonist with a well-established role in head induction during development. Numerous studies have emerged implicating Dkk1 in various malignancies and neurodegenerative diseases through an unknown mechanism. Using zebrafish gastrulation as a model for collective cell migration, we unveil such a mechanism, identifying a role for Dkk1 in control of cell connectivity and polarity in vivo, independent of its known function. We find that Dkk1 localizes to adhesion complexes at the plasma membrane and regions of concentrated actomyosin, suggesting a direct involvement in regulation of local cell adhesion. Our results show that Dkk1 represses cell polarization and integrity of cell-cell adhesion, independently of its impact on β-catenin protein degradation. Concurrently, Dkk1 prevents nuclear localization of β-catenin by restricting its distribution to a discrete submembrane pool. We propose that redistribution of cytosolic β-catenin by Dkk1 concomitantly drives repression of cell adhesion and inhibits β-catenin-dependent transcriptional output. [Display omitted] •Dkk1 localizes to adhesion complexes in vivo•Dkk1 signaling controls cell-cell connectivity and polarity•Cell interaction control is independent of β-catenin transcriptional output and Wnt/PCP•Dkk1 sequesters β-catenin at the plasma membrane In this study, Johansson and colleagues show that Dkk1 controls cell migration, polarity, and adhesion independently of its known function in fate specification and modulation of Wnt/PCP signaling. Dkk1 localizes to cell adhesion complexes and polarized actomyosin in vivo and sequesters β-catenin to a distinct submembrane pool.